H-Cube – The next generation in Hydrogenation Asynt Ltd.

H-Cube – Continuous Flow Hydrogenator Reaction Cube Concept Integrated compact flow reactors designed to have FOUR main advantages over conventional reactors. Improved Safety Faster Optimization Continuous Flow Automation Reduced Size Developed by Thales Nanotechnology (Partner company of Comgenex)

H-Cube – Continuous Flow System Product HPLC pump flows a continuous stream of solvent into reactor. Hydrogen generated from electrolysis of water Hydrogen is mixed with sample, heated and passed through a catalyst cartridge. Up to 100°C and 100 bar. (1 bar=14.5 psi) Hydrogenated product emerges continuously into reaction vial.

H-Cube System-Monitoring Screen Touch Screen operated Easy setting of pressure and temperature Control flow rate of HPLC pump Displays safety messages No lengthy set-up/shut down procedure

Hydrogenation Process H2/Substrate Mixer CatCart Heater Bubble Detector CatCart Holder Pressure Detector Back -pressure valve t=2 min t = 0

Catalyst System Catalyst contained in sealed disposable cartridges No scale-up issues No filtration necessary 10mg to 100 g scale Catalysts used: 10% Pd/C , 5% Pd/C Raney Nickel / Raney Cobalt 20% Pd(OH)2/C 10% Pt/C , 5% Pt/C Sulfided 5% Rh/C , 5% Rh/Al2O3 5% Pd/CaCO3 with lead (Lindlar’s Catalyst) 30mm

How does H-Cube compare to Batch Reactor? Nitro reduction tried on H-Cube and batch reactor. 2 minutes reaction time 100% conversion with H-Cube vs. <2% with batch reactor Higher active surface with packed column cartridges

Reductions Deprotection Deuteration Nitro group Nitrile group Imine Reaction Examples Reductions Nitro group Nitrile group Imine Heterocycle C=C bond Alkyne Dehalogenation Desulphurization Oxime Deprotection N-benzyl O-benzyl cBz Deuteration

Reaction Conditions 0.05M – 0.2M Solution in organic solvent, acetic acid or NH3/MeOH Choose CatCart (Catalyst and size) Set flow rate between 1ml/min and 3ml/min Set Pressure 1bar – 100bar Set Temperature 25-100 C Set Mode Controlled mode Full H2 mode No H2 mode (introduce a different gas) How much throughput? If RMM = 200 Worst case 1ml/min, 0.05M, 3mmol/hour (600mg) Best Case 3ml/min, 0.2M, 36mmol/hour (7.2g)

Catalyst Recycling H-Cube conditions: 0.1M, [50:50] EtOAc:EtOH, ~1 bar, 30 oC, 1 mL/min; Total material processed = 30x 10 fractions = 30 mmol = 4.85 g with 140mg Pd/C

Validation reactions 10% Pd/C, 60˚C, 1 bar Yield:>90% Raney Ni, 80˚C, 80 bar Yield: 90% 10% Pd/C, RT, 1 bar Yield: 86-89% Raney Ni, 70°C, 50 bar Yield:>85%

O-Debenzylation using the Thales H-Cube: a study of catalyst capacity & deactivation

Automated High-throughput Hydrogenation H-Cube integrated into CAVRO work station Automated injection and collection Timed injections, link to UV detector possible

H-Cube vs Traditional Batch Systems Parameter H-Cube Batch Systems Time to set-up reaction 10 minutes 30 minutes Catalyst Separation None required Filtration- Hazardous Reaction analysis 2 minutes After reaction Time taken to set up new reaction 5 minutes 60 minutes High-throughput library capability Potential for automated system Not possible Specialist Lab Required? Can use in normal laboratory Separate hydrogenation laboratory

Advantages of H-Cube Safer… Smaller… Faster… No hydrogen cylinders necessary Uses deionised water No filtration of catalyst necessary Only µmolar quantities react at any one time Smaller… H-Cube footprint is less than 0.3m3 Easy storage Scaleable reactions from mg to 100g Faster… Monitor reaction progress after 2 minutes! 30 reaction conditions can be validated in less than a half day. Simple to use, minimal training required

Acknowledgements Richard Jones, Thales Nanotechnology Mark Ladlow, GSK Cambridge